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Article ; Online: Targeting mitotic regulators in cancer as a strategy to enhance immune recognition.

Gregorczyk, Mateusz / Parkes, Eileen E

2023 Volume 132, Page(s) 103583

Abstract: Eukaryotic DNA has evolved to be enclosed within the nucleus to protect the cellular genome from autoinflammatory responses driven by the immunogenic nature of cytoplasmic DNA. Cyclic GMP-AMP Synthase (cGAS) is the cytoplasmic dsDNA sensor, which upon ... ...

Abstract	Eukaryotic DNA has evolved to be enclosed within the nucleus to protect the cellular genome from autoinflammatory responses driven by the immunogenic nature of cytoplasmic DNA. Cyclic GMP-AMP Synthase (cGAS) is the cytoplasmic dsDNA sensor, which upon activation of Stimulator of Interferon Genes (STING), mediates production of pro-inflammatory interferons (IFNs) and interferon stimulated genes (ISGs). However, although this pathway is crucial in detection of viral and microbial genetic material, cytoplasmic DNA is not always of foreign origin. It is now recognised that specifically in genomic instability, a hallmark of cancer, extranuclear material in the form of micronuclei (MN) can be generated as a result of unresolved DNA lesions during mitosis. Activation of cGAS-STING in cancer has been shown to regulate numerous tumour-immune interactions such as acquisition of 'immunologically hot' phenotype which stimulates immune-mediated elimination of transformed cells. Nonetheless, a significant percentage of poorly prognostic cancers is 'immunologically cold'. As this state has been linked with low proportion of tumour-infiltrating lymphocytes (TILs), improving immunogenicity of cold tumours could be clinically relevant by exhibiting synergy with immunotherapy. This review aims to present how inhibition of vital mitotic regulators could provoke cGAS-STING response in cancer and improve the efficacy of current immunotherapy regimens.
MeSH term(s)	Humans ; Neoplasms/pathology ; DNA/metabolism ; Cytoplasm/metabolism ; Interferons ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism
Chemical Substances	DNA (9007-49-2) ; Interferons (9008-11-1) ; Nucleotidyltransferases (EC 2.7.7.-)
Language	English
Publishing date	2023-10-18
Publishing country	Netherlands
Document type	Review ; Journal Article
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2023.103583
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Zs.A 5555: Show issues

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Article ; Online: cGAS-STING signalling in cancer: striking a balance with chromosomal instability.

Beernaert, Bruno / Parkes, Eileen E

Biochemical Society transactions

2023 Volume 51, Issue 2, Page(s) 539–555

Abstract: Chromosomal instability (CIN) is a hallmark of cancer that drives tumour evolution. It is now recognised that CIN in cancer leads to the constitutive production of misplaced DNA in the form of micronuclei and chromatin bridges. These structures are ... ...

Abstract	Chromosomal instability (CIN) is a hallmark of cancer that drives tumour evolution. It is now recognised that CIN in cancer leads to the constitutive production of misplaced DNA in the form of micronuclei and chromatin bridges. These structures are detected by the nucleic acid sensor cGAS, leading to the production of the second messenger 2'3'-cGAMP and activation of the critical hub of innate immune signalling STING. Activation of this immune pathway should instigate the influx and activation of immune cells, resulting in the eradication of cancer cells. That this does not universally occur in the context of CIN remains an unanswered paradox in cancer. Instead, CIN-high cancers are notably adept at immune evasion and are highly metastatic with typically poor outcomes. In this review, we discuss the diverse facets of the cGAS-STING signalling pathway, including emerging roles in homeostatic processes and their intersection with genome stability regulation, its role as a driver of chronic pro-tumour inflammation, and crosstalk with the tumour microenvironment, which may collectively underlie its apparent maintenance in cancers. A better understanding of the mechanisms whereby this immune surveillance pathway is commandeered by chromosomally unstable cancers is critical to the identification of new vulnerabilities for therapeutic exploitation.
MeSH term(s)	Humans ; Chromosomal Instability ; Immunity, Innate/genetics ; Inflammation ; Neoplasms/genetics ; Neoplasms/metabolism ; Nucleotidyltransferases ; Signal Transduction ; Tumor Microenvironment
Chemical Substances	Nucleotidyltransferases (EC 2.7.7.-) ; cGAS protein, human (EC 2.7.7.-) ; STING1 protein, human
Language	English
Publishing date	2023-03-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20220838
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Zs.A 944: Show issues

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Article ; Online: When breaks get hot: inflammatory signaling in BRCA1/2-mutant cancers.

van Vugt, Marcel A T M / Parkes, Eileen E

Trends in cancer

2022 Volume 8, Issue 3, Page(s) 174–189

Abstract: Genomic instability and inflammation are intricately connected hallmark features of cancer. DNA repair defects due to BRCA1/2 mutation instigate immune signaling through the cGAS/STING pathway. The subsequent inflammatory signaling provides both tumor- ... ...

Abstract	Genomic instability and inflammation are intricately connected hallmark features of cancer. DNA repair defects due to BRCA1/2 mutation instigate immune signaling through the cGAS/STING pathway. The subsequent inflammatory signaling provides both tumor-suppressive as well as tumor-promoting traits. To prevent clearance by the immune system, genomically instable cancer cells need to adapt to escape immune surveillance. Currently, it is unclear how genomically unstable cancers, including BRCA1/2-mutant tumors, are rewired to escape immune clearance. Here, we summarize the mechanisms by which genomic instability triggers inflammatory signaling and describe adaptive mechanisms by which cancer cells can 'fly under the radar' of the immune system. Additionally, we discuss how therapeutic activation of the immune system may improve treatment of genomically instable cancers.
MeSH term(s)	BRCA1 Protein/genetics ; BRCA1 Protein/metabolism ; DNA Repair/genetics ; Genomic Instability ; Humans ; Inflammation/genetics ; Neoplasms/therapy ; Signal Transduction/genetics
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human
Language	English
Publishing date	2022-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2021.12.003
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Article: Eileen Parkes on Why Cancer Researchers Are Excited About STING Agonists.

Parkes, Eileen

Oncology (Williston Park, N.Y.)

2018 Volume 32, Issue 8, Page(s) 402–403

MeSH term(s)	Clinical Trials as Topic ; Humans ; Immunity, Innate ; Interferons/genetics ; Membrane Proteins/agonists ; Membrane Proteins/physiology ; Neoplasms/drug therapy ; Precision Medicine ; Signal Transduction/physiology
Chemical Substances	Membrane Proteins ; Interferons (9008-11-1)
Language	English
Publishing date	2018-08-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	1067950-9
ISSN	0890-9091
ISSN	0890-9091
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Zs.A 3168: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 372: Show issues

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Article ; Online: Make it easier for me to deliver childcare at conferences.

Parkes, Eileen

Nature

2018 Volume 564, Issue 7736, Page(s) S89

MeSH term(s)	Child ; Child Care ; Congresses as Topic ; Humans
Language	English
Publishing date	2018-12-19
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/d41586-018-07783-2
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 9: Show issues
Zs.MO 244: Show issues

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Article: My Signature Scent.

Parkes, Eileen

Oncology (Williston Park, N.Y.)

2018 Volume 32, Issue 3, Page(s) 96–97

MeSH term(s)	Adult ; Humans ; Male ; Stomach Neoplasms/diagnostic imaging ; Stomach Neoplasms/therapy ; Tomography, X-Ray Computed
Language	English
Publishing date	2018--15
Publishing country	United States
Document type	Journal Article
ZDB-ID	1067950-9
ISSN	0890-9091
ISSN	0890-9091
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 3168: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 372: Show issues

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Article ; Online: Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer.

Parkes, Eileen E / Kennedy, Richard D

The oncologist

2016 Volume 21, Issue 5, Page(s) 586–593

Abstract: Unlabelled: : High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) ...

Abstract	Unlabelled: : High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) inhibitors in targeting tumors with deficiencies in this repair pathway by loss of BRCA1/2, ovarian tumors could be an attractive population for clinical application of this therapy. PARP inhibitors have moved into clinical practice in the past few years, with approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past 2 years. The U.S. FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. In order to widen the ovarian cancer patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. Additionally, a better understanding of the toxicity profile is needed if PARP inhibitors are to be used in the curative, rather than the palliative, setting. We reviewed the development of PARP inhibitors in phase I-III clinical trials, including combination trials of PARP inhibitors and chemotherapy/antiangiogenics, the approval for these agents, the mechanisms of resistance, and the outstanding issues, including the development of biomarkers and the rate of long-term hematologic toxicities with these agents. Implications for practice: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has recently received approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA), with a second agent (rucaparib) likely to be approved in the near future. However, the patient population with potential benefit from PARP inhibitors is likely wider than that of germline BRCA mutation-associated disease, and biomarkers are in development to enable the selection of patients with the potential for clinical benefit from these agents. Questions remain regarding the toxicities of PARP inhibitors, limiting the use of these agents in the prophylactic or adjuvant setting until more information is available. The indications for olaparib as indicated by the FDA and EMA are reviewed.
MeSH term(s)	Biomarkers ; Clinical Trials as Topic ; Drug Resistance, Neoplasm ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Humans ; Mutation ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Phthalazines/therapeutic use ; Piperazines/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
Chemical Substances	Biomarkers ; Phthalazines ; Piperazines ; Poly(ADP-ribose) Polymerase Inhibitors ; olaparib (WOH1JD9AR8)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1634/theoncologist.2015-0438
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Zs.A 4845: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 494: Show issues

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Article: DNA Repair Deficiency in Breast Cancer: Opportunities for Immunotherapy.

Gilmore, Elaine / McCabe, Nuala / Kennedy, Richard D / Parkes, Eileen E

Journal of oncology

2019 Volume 2019, Page(s) 4325105

Abstract: Historically the development of anticancer treatments has been focused on their effect on tumor cells alone. However, newer treatments have shifted attention to targets on immune cells, resulting in dramatic responses. The effect of DNA repair deficiency ...

Abstract	Historically the development of anticancer treatments has been focused on their effect on tumor cells alone. However, newer treatments have shifted attention to targets on immune cells, resulting in dramatic responses. The effect of DNA repair deficiency on the microenvironment remains an area of key interest. Moreover, established therapies such as DNA damaging treatments such as chemotherapy and PARP inhibitors further modify the tumor microenvironment. Here we describe DNA repair pathways in breast cancer and activation of innate immune pathways in DNA repair deficiency, in particular, the STING (STimulator of INterferon Genes) pathway. Breast tumors with DNA repair deficiency are associated with upregulation of immune checkpoints including PD-L1 (Programmed Death Ligand-1) and may represent a target population for single agent or combination immunotherapy treatment.
Language	English
Publishing date	2019-06-19
Publishing country	Egypt
Document type	Journal Article ; Review
ZDB-ID	2461349-6
ISSN	1687-8469 ; 1687-8450
ISSN (online)	1687-8469
ISSN	1687-8450
DOI	10.1155/2019/4325105
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Article ; Online: Development of Immunotherapy Combination Strategies in Cancer.

Yap, Timothy A / Parkes, Eileen E / Peng, Weiyi / Moyers, Justin T / Curran, Michael A / Tawbi, Hussein A

Cancer discovery

2021 Volume 11, Issue 6, Page(s) 1368–1397

Abstract: Harnessing the immune system to treat cancer through inhibitors of CTLA4 and PD-L1 has revolutionized the landscape of cancer. Rational combination strategies aim to enhance the antitumor effects of immunotherapies, but require a deep understanding of ... ...

Abstract	Harnessing the immune system to treat cancer through inhibitors of CTLA4 and PD-L1 has revolutionized the landscape of cancer. Rational combination strategies aim to enhance the antitumor effects of immunotherapies, but require a deep understanding of the mechanistic underpinnings of the immune system and robust preclinical and clinical drug development strategies. We review the current approved immunotherapy combinations, before discussing promising combinatorial approaches in clinical trials and detailing innovative preclinical model systems being used to develop rational combinations. We also discuss the promise of high-order immunotherapy combinations, as well as novel biomarker and combinatorial trial strategies. SIGNIFICANCE: Although immune-checkpoint inhibitors are approved as dual checkpoint strategies, and in combination with cytotoxic chemotherapy and angiogenesis inhibitors for multiple cancers, patient benefit remains limited. Innovative approaches are required to guide the development of novel immunotherapy combinations, ranging from improvements in preclinical tumor model systems to biomarker-driven trial strategies.
MeSH term(s)	Drug Development ; Drug Therapy, Combination ; Humans ; Immune Checkpoint Inhibitors/administration & dosage ; Immune Checkpoint Inhibitors/therapeutic use ; Immunotherapy ; Neoplasms/drug therapy
Chemical Substances	Immune Checkpoint Inhibitors
Language	English
Publishing date	2021-04-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-20-1209
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Zs.A 6916: Show issues

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Article ; Online: Reactivation of low avidity tumor-specific CD8

Sugiyarto, Gessa / Lau, Doreen / Hill, Samuel Luke / Arcia-Anaya, David / Boulanger, Denise S M / Parkes, Eileen / James, Edward / Elliott, Tim

Journal for immunotherapy of cancer

2023 Volume 11, Issue 8

Abstract: Background: CD8: Methods: CT26 models were treated with anti-PD-1 on days 3, 6 and 9 following subcutaneous tumor implantation generating variable responses during early tumor development. Tetramer staining was performed to determine the frequency ... ...

Abstract	Background: CD8 Methods: CT26 models were treated with anti-PD-1 on days 3, 6 and 9 following subcutaneous tumor implantation generating variable responses during early tumor development. Tetramer staining was performed to determine the frequency and avidity of CD8 Results: Treatment success with anti-PD-1 was associated with the preferential expansion of low avidity (Tet Conclusions: Targeting subdominant T cell responses with lower avidity against pMHC affinity neoepitopes showed potential for improving PD-1 immunotherapy. Future interventions may consider expanding low avidity populations via vaccination or adoptive transfer.
MeSH term(s)	Humans ; Adoptive Transfer ; Apoptosis ; CD8-Positive T-Lymphocytes ; Neoplasms/drug therapy ; Receptors, Antigen, T-Cell ; Immunotherapy
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-08-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-007114
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